This gene encodes adenylate cyclase-activating polypeptide 1. Mediated by adenylate cyclase-activating polypeptide 1 receptors, this polypeptide stimulates adenylate cyclase and subsequently increases the cAMP level in target cells. Adenylate cyclase-activating polypeptide 1 not only is a hypophysiotropic hormone (i.e. a substance that induces activity in the hypophysis), but also functions as a neurotransmitter and neuromodulator. In addition, it plays a role in paracrine and autocrine regulation of certain types of cells. This gene is composed of five exons. Exons 1 and 2 encode the 5' UTR and signal peptide, respectively; exon 4 encodes an adenylate cyclase-activating polypeptide 1-related peptide; and exon 5 encodes the mature peptide and 3' UTR. This gene encodes three different mature peptides, including two isotypes: a shorter form and a longer form.
A version of this gene has been associated with post-traumatic stress disorder (PTSD) in women (but not men). This disorder involves a maladaptive psychological response to traumatic, i.e. existence-threatening, events. Ressler et al. identified an association of a SNP in the gene coding for pituitary adenylate cyclase-activating polypeptide (PACAP), implicating this peptide and its receptor (PAC1) in PTSD.
Both isoforms of PACAP (PACAP-38 and PACAP-27) have been implicated in migraine pathogenesis. A Danish research group led by Dr. Messoud Ashina found that intravenous infusion of PACAP-38 induced migraine attacks in 58% of people with migraine, whilst the corresponding migraine induction rate was 55% for PACAP-27. Treatments with monoclonal antibodies have been investigated to target PACAP or its receptors for the treatment of primary headache disorders. Alder BioPharmaceuticals's ALD1910, which targets the peptide, began a phase I study in October 2019.Amgen's AMG-301, which targets the PAC1 receptor, failed to show greater efficacy than placebo in phase II trials.
^Felley CP, Qian JM, Mantey S, Pradhan T, Jensen RT (December 1992). "Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release". The American Journal of Physiology. 263 (6 Pt 1): G901-7. doi:10.1152/ajpgi.1992.263.6.G901. PMID1335692.
Felley CP, Qian JM, Mantey S, Pradhan T, Jensen RT (December 1992). "Chief cells possess a receptor with high affinity for PACAP and VIP that stimulates pepsinogen release". The American Journal of Physiology. 263 (6 Pt 1): G901-7. doi:10.1152/ajpgi.1992.263.6.G901. PMID1335692.
Geng L, Ju G (January 1997). "[The discovery of pituitary adenylate cyclase activating polypeptide (PACAP) and its research progress]". Sheng Li Ke Xue Jin Zhan [Progress in Physiology]. 28 (1): 29–34. PMID10921074.
Gourlet P, Vandermeers A, Robberecht P, Deschodt-Lanckman M (August 1997). "Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP-27, but not PACAP-38) degradation by the neutral endopeptidase EC 188.8.131.52". Biochemical Pharmacology. 54 (4): 509–15. doi:10.1016/S0006-2952(97)00207-4. PMID9313778.
Inooka H, Endo S, Kitada C, Mizuta E, Fujino M (November 1992). "Pituitary adenylate cyclase activating polypeptide (PACAP) with 27 residues. Conformation determined by 1H NMR and CD spectroscopies and distance geometry in 25% methanol solution". International Journal of Peptide and Protein Research. 40 (5): 456–64. doi:10.1111/j.1399-3011.1992.tb00324.x. PMID1483839.
Kimura C, Ohkubo S, Ogi K, Hosoya M, Itoh Y, Onda H, et al. (January 1990). "A novel peptide which stimulates adenylate cyclase: molecular cloning and characterization of the ovine and human cDNAs". Biochemical and Biophysical Research Communications. 166 (1): 81–9. doi:10.1016/0006-291X(90)91914-E. PMID2302217.
Nakata M, Yada T (2007). "PACAP in the glucose and energy homeostasis: physiological role and therapeutic potential". Current Pharmaceutical Design. 13 (11): 1105–12. doi:10.2174/138161207780618948. PMID17430174.
Ohkubo S, Kimura C, Ogi K, Okazaki K, Hosoya M, Onda H, et al. (1992). "Primary structure and characterization of the precursor to human pituitary adenylate cyclase activating polypeptide". DNA and Cell Biology. 11 (1): 21–30. doi:10.1089/dna.1992.11.21. PMID1739432.
Pérez-Jurado LA, Francke U (June 1993). "Dinucleotide repeat polymorphism at the human pituitary adenylate cyclase activating polypeptide (PACAP) gene". Human Molecular Genetics. 2 (6): 827. doi:10.1093/hmg/2.6.827-a. PMID8353512.
Vaudry D, Falluel-Morel A, Bourgault S, Basille M, Burel D, Wurtz O, et al. (September 2009). "Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery". Pharmacological Reviews. 61 (3): 283–357. doi:10.1124/pr.109.001370. PMID19805477. S2CID5739004.
Waschek JA (2002). "Multiple actions of pituitary adenylyl cyclase activating peptide in nervous system development and regeneration". Developmental Neuroscience. 24 (1): 14–23. doi:10.1159/000064942. PMID12145407. S2CID22281905.
Weber B, Riess O, Daneshvar H, Graham R, Hayden MR (June 1993). "(CA)n-dinucleotide repeat at the PDEB locus in 4p16.3". Human Molecular Genetics. 2 (6): 827. doi:10.1093/hmg/2.6.827. PMID8394765.
Wray V, Kakoschke C, Nokihara K, Naruse S (June 1993). "Solution structure of pituitary adenylate cyclase activating polypeptide by nuclear magnetic resonance spectroscopy". Biochemistry. 32 (22): 5832–41. doi:10.1021/bi00073a016. PMID8504103.